An analysis of the immune response to pneumococcal proteins expressed during carriage in humans may reveal potential protein vaccine candidates. Half of the subjects in an experimental model of human carriage became colonized for 27-122 days; the other subjects were naturally resistant to colonization by the type 23F pneumococcus. IgG antibodies that recognized a 22 kD band (subsequently identified as the truncated N-terminus of pneumococcal surface protein A (PspA)) appeared after inoculation with pneumococcus in colonized subjects (6 of 7), while in all uncolonized subjects (7 of 7), PspA-specific antibodies were present prior to inoculation, suggesting a correlation between presence of PspA-specific IgG and resistance to colonization. The human serum and secretory antibody response to PspA was further elucidated by ELISA. This proposal examines the potential for PspA as a vaccine candidate against pneumococcal colonization and utilizes rational vaccine design based on the susceptibility to carriage in humans to identify novel vaccine candidates as well as to evaluate previously described vaccine antigens. In addition, the conservation of PspA expression in clinical isolates of pneumococcus will be examined to determine the effectiveness of a protein vaccine based soley on PspA. [unreadable] [unreadable]